rs121918416

Variant names:

• chr5-151851440-C-T
• rs121918416
• NM_000171.4:c.862G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000171.4(GLRA1):​c.862G>A​(p.Val288Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRA1 NM_000171.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:2 U:1
• Conservation: PhyloP100: 7.73
• Publications: 5 publications found

Genes affected

GLRA1 (HGNC:4326): (glycine receptor alpha 1) The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

GLRA1 Gene-Disease associations (from GenCC):

• hyperekplexia 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000171.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 5-151851440-C-T is Pathogenic according to our data. Variant chr5-151851440-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16070.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRA1	NM_000171.4	c.862G>A	p.Val288Met	missense_variant	Exon 7 of 9	ENST00000274576.9	NP_000162.2
GLRA1	NM_001146040.2	c.862G>A	p.Val288Met	missense_variant	Exon 7 of 9		NP_001139512.1
GLRA1	NM_001292000.2	c.613G>A	p.Val205Met	missense_variant	Exon 6 of 8		NP_001278929.1
GLRA1	XM_047417105.1	c.910G>A	p.Val304Met	missense_variant	Exon 7 of 9		XP_047273061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRA1	ENST00000274576.9	c.862G>A	p.Val288Met	missense_variant	Exon 7 of 9	1	NM_000171.4	ENSP00000274576.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 1 Pathogenic:2

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 04, 2012

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

GLRA1-related disorder Uncertain:1

Feb 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GLRA1 c.862G>A variant is predicted to result in the amino acid substitution p.Val288Met. This variant has been reported in an individual with hyperekplexia; the variant was inherited from the individual's father, though the only phenotype noted in the father was an exaggerated startle response (del Giudice et al. 2001. PubMed ID: 11781706). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0	.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.94
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.88
gMVP		0.89
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918416; hg19: chr5-151231001;